Fibrinolytics

1. Fibrinolytics

2. Fibrinolytics • These are drugs used to lyse thrombi/ clot to recanalyse occluded blood vessels (mainly coronary artery) • Thrombolytics

3. Mechanism of fibrinolysis plasminogen ↓ plasmin ↓ fibrin digestion ↓ clot dissolution tissue plasminogen activator

4. Fibrinolytic Drugs • Streptokinase • Alteplase, Reteplase,Tenecteplase • Urokinase • Anistreplase • Recombinant single chain Urokinase plasminogen activator

5. Streptokinase • Protein derived from beta-hemolytic streptococcus • Molecular weight: 47000 Daltons • It forms a complex with plasminogen , then it converts plasminogen to plasmin • Half life: 30 - 80 min • Administration : 1.5 MU IV over 60 min • Loading dose is necessary

6. Antigenic : hypersensitivity reactions anaphylaxis • Bleeding • Fever • Hypotension • arrhythmia

7. Anistreplase • Anisoylated plasminogen streptokinase activator complex • Prodrug of streptokinase • Molecular weight: 59042.3 g/mol • Half life : 90 min • Administration: 2 MU IV bolus

8. Alteplase & Duteplase • Recombinant t-PA • Produced by recombinant DNA technology from human tissue culture • Alteplase: single chain • Duteplase: double chain • Activity enhanced in presence of fibrin

9. Activates plasminogen bound to fibrin. • Non-antigenic • Short half life • IV infusion • Nausea, mild hypotension, fever

10. Urokinase • Prepared from cultures of human embryonic kidney cells • Acts directly as plasminogen activator • Half life: 15-20 min • 1.5 MU bolus IV; then 1.5 MU IV over 1 hour • Non antigenic • Bleeding; Hypotension (rarely)

11. Clinical Uses • Acute Myocardial Infarction • First line drugs • Fibrinolytic therapy should be instituted within 12 hour of symptom onset. • Heparin + Aspirin is generally started concurrently or soon after thrombolysis to prevent re-occlusion

12. Clinical Uses 2. Pulmonary Embolism • Heparin therapy is the mainstay of treatment • Thrombolytic agent : adjuvant • Lung function preserved

13. Clinical Uses 3. Deep vein thrombosis • Use in early stages appears to be better than anticoagulant therapy • Preserve venous valves • Reduce risk of pulmonary embolism • Up to 60% patients can be successfully treated.

14. Clinical Uses 4. Acute peripheral arterial occlusion • Particularly used for dissolving occlusion of small arteries that cannot be surgically treated • Given within 72 hours.

15. Antiplatelet drugs

16. Platelets (thrombocytes) • Formed in the bone marrow from cells called megakaryocytes • Have no nucleus, but can secrete a variety of substances & can also contract (because they contain actin & myosin) • Normal concentration in the blood is about 2,50,000 per cubic millimeter • Remain functional for about 7 - 10 days (after which they are removed from the blood by macrophages in the spleen & liver) • Play an important role in hemostasis (preventing blood loss)

17. Antiplatelet Drugs • Prostacyclin PGI2 : Epoprostanol • Inhibitors of TXA2 formation: Aspirin • ADP receptor antagonists: Ticlopidine, Clopidogrel • Phosphodiesterase inhibitor: Dipyridamole • Glycoprotein IIb/ IIIa antagonist: Abciximab

18. Prostacyclin PGI2 • Naturally occurring potent vasodilator • Produced by walls of blood vessels • Inhibits platelet aggregation by stimulating adenylcyclase • Epoprostanol- aPGI2 analogue is used for preventing platelet aggregation during haemodialysis • Hypotension,tachycardia,headache,flushing

19. Aspirin • Drug in the family of salicylates. • Often used as an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory . • Has also an antiplatelet (“blood-thinning”) effect . • Low-dose(75-150mg) aspirin acetylates & thus inactivates COX & thromboxane synthetase enzyme irreversibly & blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation

20. ___ ASPIRIN Prostaglandins Thromboxane synthetase TXA2 Inhibit Adenyl cyclase ↓ Platelet cAMP ↑ Platelet aggregation

21. Aspirin induced prolongation of bleeding time lasts 5-7days. • It also inhibits PGI2 synthesis in vessel wall. However since endothelial cells can synthesize fresh enzyme, activity returns rapidly. • low-dose aspirin increases the risk of major bleeding . • Episodes of peptic ulcer bleeds in people above 60 years are seen in prophylactic aspirin.

22. Dipyridamole • Vasodilator drug  angina pectoris • This drug blocks platelet Phosphodiesterase enzyme and inhibit adenosine uptake, leading to an increase in cAMP which in turn inhibits platelet aggregation. • used alone  no significant clinical effect • Potentiates the action of warfarin. • Along with warfarin it is used to decrease the incidence of thromboembolism in patients with prosthetic heart valves. • 100 mg 4 times a day.

23. Ticlopidine • Thienopyridine family. • ADP receptor (P2Y12) antagonist • By altering the surface receptors on platelets it blocks adenylcyclase inhibition by ADP leading to increased cAMP. • Prolongs bleeding time. • Synergistic action with aspirin .

24. Pharmacokinetic data • Well absorbed orally Bioavailability>80% Protein binding: 98% Metabolism: Hepatic Half life: 12 hours (single dose) 4 to 5 days (after repeated dosing) Excretion: Renal and fecal

25. Adverse Effects • Neutropenia • Agranulocytosis • Thrombocytopenic purpura • Rashes • Diarrhea • Jaundice

26. Clopidogrel • Newer congener to Ticlopidine • Pharmacokinetic data • Well absorbed orally • Bioavailability>50% • Metabolism: hepatic • Half life: 7–8 hours • Excretion: 50% renal 46% biliary • Well Tolerated. • Diarrhea, epigastric pain, rashes • Combined with aspirin in stented patients.

27. Abciximab • Glycoprotein IIb / IIIa receptor antagonist. • Monoclonal antibody against platelet receptor. • Given IV, platelet aggregation is inhibited for 12- 24 hours • Used along with aspirin & heparin during coronary angioplasty. • Non – antigenic. • Hemorrhage . • Thrombocytopenia, constipation, arrhythmia.

28. Clinical Uses 1.Myocardial infarction • Low dose aspirin started immediately after MI prevents reinfarction and reduce mortality. • Use with or with out Heparin • Clopidogrel/Ticlopidine are alternatives

29. Clinical Uses 2.Unstable Angina • Aspirin (100- 150 mg/day) given along with Heparin followed by Warfarin decreases risk of MI & sudden death in patients with unstable angina. • Clopidogrel/Ticlopidine are alternatives/adjuvant to aspirin.

30. Clinical Uses 3.Cerebrovascular disease • Aspirin has been used to prevent transient ischemic attacks of stroke in patients with cerebrovascular disease, although aspirin do not alter the cause of stroke

31. Clinical Uses 4.Prosthetic heart valves • Antiplatelet drugs + warfarin decreases the formation of micro thrombi on artificial heart valves. • Aspirin most effective; but increase risk of bleeding with warfarin • Dipyridamole is used along with warfarin 5. Venous Thromboembolism • Antiplatelet drugs  prophylactic use